Proteins are encoded by stored inherited genetic information and perform most of the catalytic and structural functions in living cells. Protein biosynthetic quality control orchestrates the elimination of newly synthesized proteins unable to achieve conformational maturation. It is of great medical importance because efficient clearance of aberrant proteins, and the lack thereof, contribute to the molecular pathogenesis associated with multiple loss-of-function and gain-of-toxic function disorders, respectively. Arguably, the system is best understood for secretory and membrane proteins that traverse compartments of the exocytic pathway prior to final deployment. Asparagine-linked oligosaccharides function as an appendage through which a small ensemble of glycan processing and recognition elements orchestrate the degradation of aberrant glycoproteins in the early exocytic pathway as a post-translational checkpoint in eukaryote genome expression. Modification of the glycans by ER mannosidase I (ERManI), when bound to nonnative protein structure, generates the degradation signal. The concentration of ERManI controls the rate, and accuracy, of substrate selection by controlling the time at which asparagine-linked glycans are modified following glycoprotein synthesis. Neither the mechanism(s) by which the concentration is controlled, or the contribution of ERManI regulation in the etiology of disease have been investigated. We have begun to uncover the regulatory pathways, and preliminary data are consistent with a model in which an elevated ERManI concentration plays a protective role by delaying the onset of liver cirrhosis associated with the accumulation of aberrant alphal-antitrypsin PI Z polymers in the ER of liver hepatocytes. Moreover, low ERManI levels coincide with development of the early-onset cirrhotic phenotype. The immediate goals are to dissect two novel regulatory pathways for ERManI, and delineate their participation in the etiology of the early- and late-onset gain-of-toxic-function disorders. The specific aims are to: (1) dissect the signals that mediate post-translational down-regulation of human ERManI, (2) characterize the link between ERManI regulation and the unfo. The findings will demonstrate how glycoprotein biosynthetic quality control can function as a disease modifier, possible diagnostic marker, and potential site for therapeutic intervention. Moreover, the study will have broad implications, and serve as a paradigm, for the investigation of numerous protein-folding diseases.